By Kevin DaviesOctober 10, 2003 | TWO YEARS AGO, a 21-year-old terminal cancer patient named Abigail Burroughs was stymied in her efforts to obtain AstraZeneca's potentially life-saving drug Iressa (gefitinib, ZD1839), which was then in clinical trials. Following her death, her father founded the nonprofit Abigail Alliance for Better Access to Developmental Drugs, and this summer sued Mark McClellan, commissioner of the FDA, and Tommy Thompson, secretary of the Department of Health and Human Services. Among the charges: FDA policies were tantamount to "a death sentence ... in violation of the guarantee of the Fifth Amendment of the U.S. Constitution against deprivation of life without due process."

But in Japan, the Iressa experience has been very different. A few months after the drug was approved in Japan (in July 2002, following a whirlwind five-month review) to treat non-small cell lung cancer (NSCLC), reports surfaced of dozens of unusual deaths, mostly as a result of interstitial pneumonia. To date, more than 25,000 Japanese patients have received the drug — and more than 200 of them have died from pneumonia-like illness.

These contrasting views of Iressa highlight the enormous stakes surrounding the development and approval of breakthrough therapies for cancer and other common diseases. Fashioned with the same kind of molecular insights as other recent cancer drugs, Iressa could command a quarter of the annual lung cancer market — worth about $2 billion per year, according to analysts [1]. Some anecdotal patient survival stories have been hugely compelling, and even The Wall Street Journal joined the FDA lobbying effort on behalf of the drug. But the largest trials so far have yielded very disappointing results, and the response in Japan has raised serious questions about not only the efficacy but also the safety of the little brown pill.

Iressa is a small-molecule tyrosine kinase inhibitor, the same class of drug as Novartis' Gleevec. It acts by targeting the epidermal growth factor receptor (EGFR), a protein overactive in many forms of cancer. (Herceptin, the Genentech monoclonal antibody used to treat aggressive forms of breast cancer, targets a related protein called Her-2.) By preventing the activation of EGFR, Iressa shuts down signaling via this protein, choking the growth of cancer cells.

Efficacy and Safety
The FDA approved Iressa in May 2003 as a third-line defense for patients who had previously received chemotherapy. The critical data for approval came from a Phase II trial of 142 NSCLC patients who had not responded to traditional chemotherapy, showing an Iressa response rate of about 13 percent. However, in a larger cohort of 2,000 previously untreated patients, the drug had proven ineffective.

An AstraZeneca spokesperson said uptake in the U.S. "has been exactly as we planned," but declined to offer more specifics.

S everal factors could account for Iressa's mediocre Phase III results, including delivering the optimum dose of the drug to the tumor, and negative interactions when co-administered with other drugs. Moreover, EGFR inhibitors may simply not work in all tumors. If patients are not selected for specific markers that predict EGFR sensitivity, it has been argued the trials should be expanded to account for the dilution effect of mixing sensitive and resistant patients [2].

Recent history underscores the value of stratifying patients in clinical trials. Herceptin and Gleevec are rationally designed cancer drugs, but unlike Iressa, the most responsive patients taking these drugs were identified prior to trials based on unequivocal expression of protein or genetic markers. Without that benefit, it is possible that the Iressa trials thus far have been underpowered to reveal a significant Phase III benefit.

Aside from establishing efficacy, AstraZeneca is participating in two major studies with Japanese researchers to settle Iressa's lingering safety concerns. One of the country's leading cancer geneticists, Yusuke Nakamura, is heading a pharmacogenomic survey of thousands of polymorphisms in 200 candidate genes to search for possible genetic associations. Another study, also based in Tokyo, is taking a proteomic "before-and-after" approach to see if administering Iressa alters the levels of circulating proteins.

The mortality rate of about 1 percent among Japanese patients taking Iressa should be considered against the fact that lung cancer claims more than 50,000 lives in that country each year. But while the investigation into the cause of the fatal lung disease continues, this summer a Japanese health ministry panel declined to endorse Iressa. In spite of numerous studies that have deemed the drug effective, the panel concluded there were insufficient data to recommend it.

The mood was summed up by an editorial in The Japan Times: "When it comes to medicine, the bottom line is simple. Use of drugs that carry a high risk of causing harmful side effects must not be allowed ... The government, pharmaceutical companies, and doctors must respect this standard and promote anti-cancer drug treatment that benefits patients."

The long-term success of Iressa could benefit tens of thousands of patients. AstraZeneca, which has seen its stock price rise 40 percent in the past 12 months, is well aware that Iressa's market could be hit hard by the expected approval next year of the rival Genentech/Roche drug, Tarceva. Meanwhile, GlaxoSmithKline and several other pharmas are devising the next generation of Iressa-like compounds for use in cancer, and they will be relying on pharmacogenomic approaches to identify responders and maximize the efficiency of future trials.

Encouraging though this is, identifying the primary cause — genetic or otherwise — of the lung disease that has tainted the rollout of Iressa must remain a top priority.